1. Field of the Invention
The present invention relates to processes for sterilizing and depyrogenating solutions and, more particularly, to a process for sterilizing and depyrogenating solutions with oxidants.
2. Description of the Prior Art
The United States Pharmacopeia's (USP) official monographs on water states that water for injection, irrigation and inhalation is chemically purified by distillation or reverse osmosis. The water, or any other parenteral solution must be sterile and must contain no more than a specified limit of fever producing pyrogens, or bacterial endotoxin. A maximum level of permissible endotoxin has been set at 0.25 endotoxin units/ml in water used for injection. Further studies have indicated, however, that the maximum of 0.25 EU/ml may be too high for some applications and, have suggested, therefore, that the permissible endotoxin level be determined on a dose basis.
Hospitals at one time prepared purified water for in-house use by distillation. Increasing energy costs and quality control requirements forced many hospitals to abandon the in-house preparation of purified water in favor of purchasing commercially prepackaged solutions. The cost of the prepackaged solutions however, can be prohibitive.
In addition to patient use, purified water is used in the pharmaceutical and microelectronics industries. Bacterial growth can create defects on semiconductors.
Bacterial endotoxin is not completely destroyed by conventional sterilization processes employing heat or filtration. Methods of chemically purifying solutions using two-stage reverse osmosis or reverse osmosis and ultrafiltration have been coupled with membrane filtration or heat to sterilize. Thus, a number of redundant, and costly, back-up systems are required to reduce the endotoxin in solution to acceptacle levels. Downstream contamination remains a possibility.
Methods for depyrogenating include heat treatment, hydrolysis with mild acetic acid or mild alkali, treatment with oxidizing agents, acetylation, hydroxylaminolysis, and reductive cleavage by lithium aluminum hydride. Some methods are satisfactory for only simple solutions. Hydrogen peroxide was shown to be an effective agent for the depyrogenation of oxypolygelatin used as a plasma substitute. Its use was extended to the depyrogenation of solutions of sodium chloride and dextrose. See Cherkin, "Destruction of Bacterial Endotoxin Pyrogenicity By Hydrogen Peroxide," 12 IMMUNOCHEMISTRY 625 (1975).
The Cherkin article indicates that the combination of hydrogen peroxide and relatively long exposure to elevated temperatures is effective for depyrogenating batches of pyrogenic solutions. Test batches injected with 0.1M H.sub.2 O.sub.2 and heated to 100.degree. C. for 1-2 hours were successfully depyrogenated. Later studies confirmed the effectiveness of hydrogen peroxide in rendering water, saline and dextrose solutions nonpyrogenic. For simple solutions, however, manganese dioxide or activated charcoal is required to remove excess peroxide.
A known method for depyrogenating a solution with hydrogen peroxide includes the steps of boiling the hydrogen peroxide-containing solution for fifteen minutes, cooling for five minutes, then boiling for one hour, then cooling to room temperature. Thereafter, an additive for destroying the hydrogen peroxide is introduced into the solution, which is again boiled for fifteen minutes, then cooled for five minutes and finally filtered. Almost two hours is required for each batch. More importantly, the oxidant removal additive can render the solution unacceptable for patient use.
There is a need for a process for rapidly sterilizing and depyrogenating solutions for patient use. There is a further need for such a process which can be used by hospitals to provide a continuous supply of sterilized and depyrogenated solutions at a reasonable cost and without expensive backup systems. Finally, there is a need for such a process in which the depyrogenating agent can be removed without contaminating the solution.